Shrews in suburbia: an application of Goodman's extinction model

An equation is applied for calculating the expected persistence time of an unstructured population of the white-toothed shrew Crocidura russula from Preverenges, a suburban area in western Switzerland. Population abundance data from March and November between 1977 and 1988 were fit to the logistic density dependence model to estimate mean population growth rate as a function of population density. The variance in mean growth rate was approximated with two different models. The largest estimated persistence time was less than a few decades, the smallest less than 10 years. The results are sensitive to the magnitude of variance in population growth rate. Deviations from the logistic density dependence model in November are quite well explained by weather variables but those in March are uncorrelated with weather variables. Variability in population growth rates measured in winter months may be better explained by behavioural mechanisms. Environmental variability, dispersal of juveniles and refugia within the range of the population may contribute to its long-term survival.

Acetaminophen increases blood pressure in patients with coronary artery disease.

BACKGROUND: Because traditional nonsteroidal antiinflammatory drugs are associated with increased risk for acute cardiovascular events, current guidelines recommend acetaminophen as the first-line analgesic of choice on the assumption of its greater cardiovascular safety. Data from randomized clinical trials prospectively addressing cardiovascular safety of acetaminophen, however, are still lacking, particularly in patients at increased cardiovascular risk. Hence, the aim of this study was to evaluate the safety of acetaminophen in patients with coronary artery disease. METHODS AND RESULTS: The 33 patients with coronary artery disease included in this randomized, double-blind, placebo-controlled, crossover study received acetaminophen (1 g TID) on top of standard cardiovascular therapy for 2 weeks. Ambulatory blood pressure, heart rate, endothelium-dependent and -independent vasodilatation, platelet function, endothelial progenitor cells, markers of the renin-angiotensin system, inflammation, and oxidative stress were determined at baseline and after each treatment period. Treatment with acetaminophen resulted in a significant increase in mean systolic (from 122.4±11.9 to 125.3±12.0 mm Hg P=0.02 versus placebo) and diastolic (from 73.2±6.9 to 75.4±7.9 mm Hg P=0.02 versus placebo) ambulatory blood pressures. On the other hand, heart rate, endothelial function, early endothelial progenitor cells, and platelet function did not change. CONCLUSIONS: This study demonstrates for the first time that acetaminophen induces a significant increase in ambulatory blood pressure in patients with coronary artery disease. Thus, the use of acetaminophen should be evaluated as rigorously as traditional nonsteroidal antiinflammatory drugs and cyclooxygenase-2 inhibitors, particularly in patients at increased cardiovascular risk. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00534651.

Multicenter Study on the Clinical Effectiveness, Pharmacokinetics, and Pharmacogenetics of Mirtazapine in Depression.

ABSTRACT: Pharmacogenetic tests and therapeutic drug monitoring may considerably improve the pharmacotherapy of depression. The aim of this study was to evaluate the relationship between the efficacy of mirtazapine (MIR) and the steady-state plasma concentrations of its enantiomers and metabolites in moderately to severely depressed patients, taking their pharmacogenetic status into account. Inpatients and outpatients (n = 45; mean age, 51 years; range, 19-79 years) with major depressive episode received MIR for 8 weeks (30 mg/d on days 1-14 and 30-45 mg/d on days 15-56). Mirtazapine treatment resulted in a significant improvement in mean Hamilton Depression Rating Scale total score at the end of the study (P < 0.0001). There was no evidence for a significant plasma concentration-clinical effectiveness relationship regarding any pharmacokinetic parameter. The enantiomers of MIR and its hydroxylated (OH-MIR) and demethylated (DMIR) metabolites in plasma samples on days 14 and 56 were influenced by sex and age. Nonsmokers (n = 28) had higher mean MIR plasma levels than smokers (n = 17): S(+)-enantiomer of MIR, 9.4 (SD, 3.9) versus 6.2 (SD, 5.5) ng/mL (P = 0.005); R(-)-enantiomer of MIR, 24.4 (SD, 6.5) versus 18.5 (SD, 4.1) ng/mL (P = 0.003). Only in nonsmokers, plasma levels of S(+)-enantiomer of MIR and metabolites depended on the CYP2D6 genotype. Therefore, high CYP1A2 activity seen in smokers seems to mask the influence of the CYP2D6 genotype. In patients presenting the CYP2B6 *6/*6 genotype (n = 8), S-OH-MIR concentrations were higher those in the other patients (n = 37). Although it is not known if S-OH-MIR is associated with the therapeutic effect of MIR, the reduction of the Hamilton scores was significantly (P = 0.016) more pronounced in the CYP2B6 *6/*6-genotyped patients at the end of the study. The role of CYP2B6 in the metabolism and effectiveness of MIR should be further investigated.

The effect of continuous positive airway pressure on total cerebral blood flow in healthy awake volunteers.

PURPOSE: Continuous positive airway pressure (CPAP) is the gold standard treatment for obstructive sleep apnea. However, the physiologic impact of CPAP on cerebral blood flow (CBF) is not well established. Ultrasound can be used to estimate CBF, but there is no widespread accepted protocol. We studied the physiologic influence of CPAP on CBF using a method integrating arterial diameter and flow velocity (FV) measurements obtained for each vessel supplying blood to the brain. METHODS: FV and lumen diameter of the left and right internal carotid, vertebral, and middle cerebral arteries were measured using duplex Doppler ultrasound with and without CPAP at 15 cm H(2)O, applied in a random order. Transcutaneous carbon dioxide (PtcCO(2)), heart rate (HR), blood pressure (BP), and oxygen saturation were monitored. Results were compared with a theoretical prediction of CBF change based on the effect of partial pressure of carbon dioxide on CBF. RESULTS: Data were obtained from 23 healthy volunteers (mean ± SD; 12 male, age 25.1 ± 2.6 years, body mass index 21.8 ± 2.0 kg/m(2)). The mean experimental and theoretical CBF decrease under CPAP was 12.5 % (p < 0.001) and 11.9 % (p < 0.001), respectively. The difference between experimental and theoretical CBF reduction was not statistically significant (3.84 ± 79 ml/min, p = 0.40). There was a significant reduction in PtcCO(2) with CPAP (p = <0.001) and a significant increase in mean BP (p = 0.0017). No significant change was observed in SaO(2) (p = 0.21) and HR (p = 0.62). CONCLUSION: Duplex Doppler ultrasound measurements of arterial diameter and FV allow for a noninvasive bedside estimation of CBF. CPAP at 15 cm H(2)O significantly decreased CBF in healthy awake volunteers. This effect appeared to be mediated predominately through the hypocapnic vasoconstriction coinciding with PCO(2) level reduction. The results suggest that CPAP should be used cautiously in patients with unstable cerebral hemodynamics.

Discordant secular trends in elevated blood pressure and obesity in children and adolescents in a rapidly developing country

BACKGROUND: The effect of the increasing prevalence of obesity on blood pressure (BP) secular trends is unclear. We analyzed BP and body mass index secular trends between 1998 and 2006 in children and adolescents of the Seychelles, a rapidly developing island state in the African region. METHODS AND RESULTS: School-based surveys were conducted annually between 1998 and 2006 among all students in 4 school grades (kindergarten and 4th, 7th, and 10th years of compulsory school). We used the Centers for Disease Control and Prevention criteria to define obesity and elevated BP. The same methods and instruments were used in all surveys. Some 25 586 children and adolescents 4 to 18 years of age contributed 43 867 observations. Although the prevalence of obesity in boys and girls increased from 5.1% and 6.0%, respectively, in 1998 to 2000 to 8.0% and 8.7% in 2004 to 2006, the prevalence of elevated BP decreased from 8.4% and 9.8% to 6.9% and 7.8%. During the interval, mean age-adjusted body mass index increased by 0.57 kg/m(2) in boys and 0.58 kg/m(2) in girls. Mean age- and height-adjusted systolic BP decreased by -3.0 mm Hg in boys and -2.8 mm Hg in girls, whereas mean diastolic BP did not change substantially in boys (-0.2 mm Hg) and increased slightly in girls (0.4 mm Hg). CONCLUSIONS: At a population level, the marked increase in the prevalence of obesity in children and adolescents in the Seychelles was not associated with a commensurate secular rise in mean BP.

Complementary effects of adenosine and angiotensin II in hypoxemia-induced renal dysfunction in the rabbit.

The acute renal effects of hypoxemia and the ability of the co-administration of an angiotensin converting enzyme inhibitor (perindoprilat) and an adenosine receptor antagonist (theophylline) to prevent these effects were assessed in anesthetized and mechanically-ventilated rabbits. Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by the clearances of para-aminohippuric acid and inulin, respectively. Each animal acted as its own control. In 8 untreated rabbits, hypoxemia induced a significant drop in mean blood pressure (-12 +/- 2%), GFR (-16 +/- 3%) and RBF (-12 +/- 3%) with a concomitant increase in renal vascular resistance (RVR) (+ 18 +/- 5%), without changes in filtration fraction (FF) (-4 +/- 2%). These results suggest the occurrence of both pre- and postglomerular vasoconstriction during the hypoxemic stress. In 7 rabbits pretreated with intravenous perindoprilat (20 microg/kg), the hypoxemia-induced changes in RBF and RVR were prevented. FF decreased significantly (-18 +/- 2%), while the drop in GFR was partially blunted. These results could be explained by the inhibition of the angiotensin-mediated efferent vasoconstriction by perindoprilat. In 7 additional rabbits, co-administration of perindoprilat and theophylline (1 mg/kg) completely prevented the hypoxemia-induced changes in RBF (+ 11 +/- 3%) and GFR (+ 2 +/- 3%), while RVR decreased significantly (-14 +/- 3%). Since adenosine and angiotensin II were both shown to participate, at least in part, in the renal changes induced by hypoxemia, the beneficial effects of perindoprilat and theophylline in this model could be mediated by complementary actions of angiotensin II and adenosine on the renal vasculature.

Performance in a complex task and breathing under odor exposure.

We investigated the influences of odor exposure on performance and on breathing measures. The task was composed of tracking, short-term memory, and peripheral reaction parts. During rest or while performing the task, 12 participants were exposed to 4 different odors in 2 intensities. The higher intensity of the malodors induced a short-term decrement in mean inspiration flow (Vi/Ti) after stimulus onset and impaired performance in the short-term memory task, as compared with control trials; no effect was found for the positively judged odors. The study suggests that a distractor as simple as a bad smell may pull a person off task, however briefly, and may result in a detriment to performance. Actual or potential applications of this research involve designing or securing tasks in such a way that a brief withdrawal of attention does not have fatal consequences.

Role of reactive hyperreninemia in blood pressure changes induced by sodium depletion in patients with refractory hypertension

Sixteen patients with refractory hypertension were submitted to vigorous sodium depletion while cardiovascular homeostasis was monitored with measurements of hormonal and hemodynamic parameters and repeat saralasin tests. This regimen resulted in a negative sodium balance by an average of 300 mEq. The loss of sodium closely correlated to the decrease of body weight (r = 0.70, p less than 0.005). Blood pressure (BP) decreased from 176/166 +/- 8/3 to 155/109 +/-6/3 mm Hg. There was a significant correlation between percent increments in plasma renin activity (PRA) and the rise in plasma norepinephrine (r = 0.68, p less than 0.05) and a close negative correlation between percent increase in PRA and the ratio of fall in mean blood pressure (MAP) per unit of weight loss (r = -0.73, p less than 0.005). Thus, patients with the least percent increase in PRA demonstrated the greatest fall in BP per unit of weight loss, indicating that relative rather than absolute elevation of renin may be the factor limiting antihypertensive efficacy of sodium depletion. Sodium depletion induced increase in peripheral resistance and decrease in cardiac output, both mostly attributable to relative hyperreninemia. Indeed, the adverse hemodynamic changes were reversed by angiotensin inhibition, during which BP normalized. It is concluded that vigorous sodium depletion complemented by angiotensin blockade or suppression with sympatholytic agents improves management of otherwise refractory hypertension.

Effects of antiresorptive agents on bone micro-architecture assessed by Trabecular Bone Score in women age 50 and older. The Manitoba Prospective Study

Antiresorptive agents such as bisphosphonates induce a rapid increase of BMD during the 1st year of treatment and a partial maintenance of bone architecture. Trabecular Bone Score (TBS), a new grey-level texture measurement that can be extracted from the DXA image, correlates with 3D parameters of bone micro-architecture. Aim: To evaluate the longitudinal effect of antiresorptive agents on spine BMD and on site-matched spine microarchitecture as assessed by TBS. Methods: From the BMD database for Province of Manitoba, Canada, we selected women age >50 with paired baseline and follow up spine DXA examinations who had not received any prior HRT or other antiresorptive drug.Women were divided in two subgroups: (1) those not receiving any HRT or antiresorptive drug during follow up (=non-users) and (2) those receiving non-HRT antiresorptive drug during follow up (=users) with high adherence (medication possession ratio >75%) from a provincial pharmacy database system. Lumbar spine TBS was derived by the Bone Disease Unit, University of Lausanne, for each spine DXA examination using anonymized files (blinded from clinical parameters and outcomes). Effects of antiresorptive treatment for users and non-users on TBS and BMD at baseline and during mean 3.7 years follow-up were compared. Results were expressed % change per year. Results: 1150 non-users and 534 users met the inclusion criteria. At baseline, users and non-users had a mean age and BMI of [62.2±7.9 vs 66.1±8.0 years] and [26.3±4.7 vs 24.7±4.0 kg/m²] respectively. Antiresorptive drugs received by users were bisphosphonates (86%), raloxifene (10%) and calcitonin (4%). Significant differences in BMD change and TBS change were seen between users and nonusers during follow-up (p<0.0001). Significant decreases in mean BMD and TBS (−0.36± 0.05% per year; −0.31±0.06% per year) were seen for non-users compared with baseline (p<0.001). A significant increase in mean BMD was seen for users compared with baseline (+1.86±0.0% per year, p<0.0018). TBS of users also increased compared with baseline (+0.20±0.08% per year, p<0.001), but more slowly than BMD. Conclusion: We observed a significant increase in spine BMD and a positive maintenance of bone micro-architecture from TBS with antiresorptive treatment, whereas the treatment naïve group lost both density and micro-architecture. TBS seems to be responsive to treatment and could be suitable for monitoring micro-architecture. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: M.-A. Krieg: None declared, A. Goertzen: None declared, W. Leslie: None declared, D. Hans Consulting fees from Medimaps.

Efficacy and safety of a phospholipid emulsion (GR270773) in Gram-negative severe sepsis: results of a phase II multicenter, randomized, placebo-controlled, dose-finding clinical trial.

OBJECTIVE: To assess the survival benefit and safety profile of low-dose (850 mg/kg) and high-dose (1350 mg/kg) phospholipid emulsion vs. placebo administered as a continuous 3-day infusion in patients with confirmed or suspected Gram-negative severe sepsis. Preclinical and ex vivo studies show that lipoproteins bind and neutralize endotoxin, and experimental animal studies demonstrate protection from septic death when lipoproteins are administered. Endotoxin neutralization correlates with the amount of phospholipid in the lipoprotein particles. DESIGN: A three-arm, randomized, blinded, placebo-controlled trial. SETTING: Conducted at 235 centers worldwide between September 2004 and April 2006. PATIENTS: A total of 1379 patients participated in the study, 598 patients received low-dose phospholipid emulsion, and 599 patients received placebo. The high-dose phospholipid emulsion arm was stopped, on the recommendation of the Independent Data Monitoring Committee, due to an increase in life-threatening serious adverse events at the fourth interim analysis and included 182 patients. MEASUREMENTS AND MAIN RESULTS: A 28-day all-cause mortality and new-onset organ failure. There was no significant treatment benefit for low- or high-dose phospholipid emulsion vs. placebo for 28-day all-cause mortality, with rates of 25.8% (p = .329), 31.3% (p = .879), and 26.9%, respectively. The rate of new-onset organ failure was not statistically different among groups at 26.3%, 31.3%, 20.4% with low- and high-dose phospholipid emulsion, and placebo, respectively (one-sided p = .992, low vs. placebo; p = .999, high vs. placebo). Of the subjects treated, 45% had microbiologically confirmed Gram-negative infections. Maximal changes in mean hemoglobin levels were reached on day 10 (-1.04 g/dL) and day 5 (-1.36 g/dL) with low- and high-dose phospholipid emulsion, respectively, and on day 14 (-0.82 g/dL) with placebo. CONCLUSIONS: Treatment with phospholipid emulsion did not reduce 28-day all-cause mortality, or reduce the onset of new organ failure in patients with suspected or confirmed Gram-negative severe sepsis.

Childhood socioeconomic position and objectively measured physical capability levels in adulthood: a systematic review and meta-analysis.

BACKGROUND: Grip strength, walking speed, chair rising and standing balance time are objective measures of physical capability that characterise current health and predict survival in older populations. Socioeconomic position (SEP) in childhood may influence the peak level of physical capability achieved in early adulthood, thereby affecting levels in later adulthood. We have undertaken a systematic review with meta-analyses to test the hypothesis that adverse childhood SEP is associated with lower levels of objectively measured physical capability in adulthood. METHODS AND FINDINGS: Relevant studies published by May 2010 were identified through literature searches using EMBASE and MEDLINE. Unpublished results were obtained from study investigators. Results were provided by all study investigators in a standard format and pooled using random-effects meta-analyses. 19 studies were included in the review. Total sample sizes in meta-analyses ranged from N = 17,215 for chair rise time to N = 1,061,855 for grip strength. Although heterogeneity was detected, there was consistent evidence in age adjusted models that lower childhood SEP was associated with modest reductions in physical capability levels in adulthood: comparing the lowest with the highest childhood SEP there was a reduction in grip strength of 0.13 standard deviations (95% CI: 0.06, 0.21), a reduction in mean walking speed of 0.07 m/s (0.05, 0.10), an increase in mean chair rise time of 6% (4%, 8%) and an odds ratio of an inability to balance for 5s of 1.26 (1.02, 1.55). Adjustment for the potential mediating factors, adult SEP and body size attenuated associations greatly. However, despite this attenuation, for walking speed and chair rise time, there was still evidence of moderate associations. CONCLUSIONS: Policies targeting socioeconomic inequalities in childhood may have additional benefits in promoting the maintenance of independence in later life.

Climatic and anthropogenic influence on the stable isotope record from bulk carbonates and ostracodes in Lake Neuchatel, Switzerland, during the last two millennia

Lake Neuchatel is a medium sized, hard-water lake, lacking varved sediments, situated in the western Swiss Lowlands at the foot of the Jura Mountains. Stable isotope data (delta(18)O and delta(13)C) from both bulk carbonate and ostracode calcite in an 81 cm long, radiocarbon-dated sediment core represent the last 1500 years of Lake Neuchatel's environmental history. Comparison between this isotopic and other palaeolimnologic data (mineralogical, geochemical, palynological, etc.) helps to differentiate between anthropogenic and natural factors most recently affecting the lake. An increase in lacustrine productivity (450-650AD ca), inferred from the positive trend in delta(13)C values of bulk carbonate, is related to medieval forest clearances and the associated nutrient budget changes. A negative trend in both the bulk carbonate and ostracode calcite delta(18)O values between approximately 1300 and 1500AD, is tentatively interpreted as due to a cooling in mean air temperature at the transition from the Medieval Warm Period to the Little Ice Age. Negative trends in bulk carbonate delta(18)O and delta(13)C values through the uppermost sediments, which have no equivalent in ostracode calcite isotopic values, are concomitant with the recent onset of eutrophication in the lake. Isotopic disequilibrium during calcite precipitation, probably due to kinetic factors in periods of high productivity is postulated as the mechanism to explain the associated negative isotopic trends, although the effect of a shift of the calcite precipitation towards the warmer months cannot be excluded.

Intraoperative cerebral perfusion in geriatric patients

Background: It is unknown whether cerebral perfusion in geriatric and younger patients under general anaesthesia differs. Methods: We compared 2 groups of patients undergoing elective major non-cardiac surgery under standardized general anaesthesia (thiopental, sevoflurane, fentanyl, atracurium). Group 1: 18-40 yrs (n = 20), Group 2: >65 yrs (n = 37). Cerebral perfusion was investigated with transcranial Doppler and near-infrared spectroscopy (NIRS). Arterial blood pressure was monitored continuously with a Finapres device. Mx, an index allowing continuous monitoring of cerebrovascular autoregulation based on the changes in mean arterial blood pressure (MAP) and cerebral blood flow velocity was calculated. Data are shown as mean } SD. Results: MAP (86 } 9.6 vs 79 } 10.9 mm Hg, p = 0.02), end-tidal concentration of sevoflurane (1.9 } 0.3 vs 1.6 } 0.3%, p <0.01), and the cerebral tissue oxygenation index measured by NIRS (72 } 4 vs 68 } 5%, p = 0.01), were significantly lower in Group 2. The end-tidal concentration of O2 was significantly higher in Group 2 (46 } 4 vs 48 } 4% p = 0.04). There were no significant differences between Group 1 and 2 for cerebral blood flow velocity (41 } 10 vs 43 } 18 cm/s), end tidal CO2 (4.7 } 0.3 vs 4.6 } 0.3 kPa) and cerebrovascular autoregulation (Mx 0.42 } 0.2 vs 0.48 } 0.2). In Group 1 35% and in Group 2 43% of the patients had an index of autoregulation suggesting disturbed cerebrovascular autoregulation (p = n.s.). Conclusions: In elderly patients under general anaesthesia with sevoflurane the cerebral tissue oxygenation index was significantly lower than in younger patients despite higher end-tidal oxygen concentrations. Our data suggest subtle differences in cerebral perfusion between geriatric and younger

Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19·2 million participants.

BACKGROUND: Underweight and severe and morbid obesity are associated with highly elevated risks of adverse health outcomes. We estimated trends in mean body-mass index (BMI), which characterises its population distribution, and in the prevalences of a complete set of BMI categories for adults in all countries. METHODS: We analysed, with use of a consistent protocol, population-based studies that had measured height and weight in adults aged 18 years and older. We applied a Bayesian hierarchical model to these data to estimate trends from 1975 to 2014 in mean BMI and in the prevalences of BMI categories (<18·5 kg/m(2) [underweight], 18·5 kg/m(2) to <20 kg/m(2), 20 kg/m(2) to <25 kg/m(2), 25 kg/m(2) to <30 kg/m(2), 30 kg/m(2) to <35 kg/m(2), 35 kg/m(2) to <40 kg/m(2), ≥40 kg/m(2) [morbid obesity]), by sex in 200 countries and territories, organised in 21 regions. We calculated the posterior probability of meeting the target of halting by 2025 the rise in obesity at its 2010 levels, if post-2000 trends continue. FINDINGS: We used 1698 population-based data sources, with more than 19·2 million adult participants (9·9 million men and 9·3 million women) in 186 of 200 countries for which estimates were made. Global age-standardised mean BMI increased from 21·7 kg/m(2) (95% credible interval 21·3-22·1) in 1975 to 24·2 kg/m(2) (24·0-24·4) in 2014 in men, and from 22·1 kg/m(2) (21·7-22·5) in 1975 to 24·4 kg/m(2) (24·2-24·6) in 2014 in women. Regional mean BMIs in 2014 for men ranged from 21·4 kg/m(2) in central Africa and south Asia to 29·2 kg/m(2) (28·6-29·8) in Polynesia and Micronesia; for women the range was from 21·8 kg/m(2) (21·4-22·3) in south Asia to 32·2 kg/m(2) (31·5-32·8) in Polynesia and Micronesia. Over these four decades, age-standardised global prevalence of underweight decreased from 13·8% (10·5-17·4) to 8·8% (7·4-10·3) in men and from 14·6% (11·6-17·9) to 9·7% (8·3-11·1) in women. South Asia had the highest prevalence of underweight in 2014, 23·4% (17·8-29·2) in men and 24·0% (18·9-29·3) in women. Age-standardised prevalence of obesity increased from 3·2% (2·4-4·1) in 1975 to 10·8% (9·7-12·0) in 2014 in men, and from 6·4% (5·1-7·8) to 14·9% (13·6-16·1) in women. 2·3% (2·0-2·7) of the world's men and 5·0% (4·4-5·6) of women were severely obese (ie, have BMI ≥35 kg/m(2)). Globally, prevalence of morbid obesity was 0·64% (0·46-0·86) in men and 1·6% (1·3-1·9) in women. INTERPRETATION: If post-2000 trends continue, the probability of meeting the global obesity target is virtually zero. Rather, if these trends continue, by 2025, global obesity prevalence will reach 18% in men and surpass 21% in women; severe obesity will surpass 6% in men and 9% in women. Nonetheless, underweight remains prevalent in the world's poorest regions, especially in south Asia. FUNDING: Wellcome Trust, Grand Challenges Canada.

Synergistic epistasis and alternative hypotheses.

Inbreeding generally results in deleterious shifts in mean fitness. If the fitness response to increasing inbreeding coefficient is non-linear, this suggests a contribution of epistasis to inbreeding depression. In a cross-breeding experiment, Salathe & Ebert (2003. J. Evol. Biol. 16: 976-985) tested and found the presence of this non-linearity in Daphnia magna. They argue that epistatic interactions cause this non-linearity. We argue here that their experimental protocol does not allow disentangling the effect of synergistic epistasis from two alternative hypotheses, namely hybrid vigour and statistical non-independence of data.